Many drugs are administered percutaneously, either intradermal, subcutaneous or intramuscular, by injection by qualified medical personnel. This involves a first step in reconstituting the drug with sterile water, a second step of loading of the syringe with an appropriate volume of the reconstituted drug, and a third step of administration to the patient by means of a sterile hypodermic needle.
This injection process can be problematic, especially in locations and conditions where technical and material resources are limited. In particular, many biologically active molecules and preparations require refrigeration during transport and storage, and failure of cold chain results in the loss of large amounts of drugs. Moreover, the need for reconstitution with sterile water can also represent a problem in cases of microbial contamination or use of incorrect volumes. The potential reuse of the syringe and hypodermic needles following administration of the drug also represents a serious risk of transmitting infectious agents such as hepatitis or human immunodeficiency virus (HIV). These problems are particularly acute in the administration of vaccines in the underdeveloped and developing world where the World Health Organization has recognized the need for alternative drug delivery methods (Jodar L et al. 1998 Revolutionising Immunisations. Genetic Engineering News 18-4; y Clements C J et al. 2004 Technologies that make administration of vaccines safer. Vaccine 22:2054-2058).
In general the alternative methods proposed to date for the percutaneos administration of drugs and vaccines solve some of the drawbacks of conventional hypodermic needles and syringes but do not appear to solve all the inconvenient in one single delivery format-device. Examples of this are device packages with colorimetric indicators that warn of the failure of the cold chain of storage. Other examples of these partial solutions are devices based on conventional needles and syringes that incorporate self-destruct mechanisms that prevent possible reuse. In general these devices are more expensive than conventional syringes and needles and do not avoid the need for refrigeration, reconstitution and requirement for skilled personnel for administration. Another approach, described for example in U.S. Pat. No. 4,891,319 is the stabilization of drugs by adding excipients, as is the case of trehalose, which avoid the need for cold chain but still require reconstitution prior to injection. To avoid this need for reconstitution, patent WO02/032402 proposes the suspension of drugs in microparticles stabilized in non-aqueous liquids that facilitate their injection. Still, the administration of these suspensions requires conventional devices incorporating hypodermic needles or complex liquid-jet devices. Other alternatives, such as proposed in WO97/48485, include the administration of drug-containing particles using “ballistic” devices. A problem with these systems is the need for delivery devices that provide considerable injection force by means of powerful springs, explosions, or high-speed liquid jets. Therefore these approaches cannot provide a means of administering drugs at the required depth by means of simple easy to use low-cost disposable devices.
An alternative method in the administration of vaccines that theoretically avoids the need for refrigeration, reconstitution, needles and complex devices, is the formulation of drugs in ready to injected solid formats. This approach has been explored in the design of high speed projectiles administered by devices that resemble firearms, and, alternatively, by slow speed penetrating “injectable needles” administered by devices in direct contact with the skin.
Examples of drug delivery by means of projectiles are incorporated in patent WO96/140351, which includes large projectiles (7×5 mm) formed by a solid plastic head and a hollow cylindrical body containing the drug. Due to their large size, as an alternative form of administration, it is suggested that the doctor or veterinarian performs an incision and manually inserts the projectile under the skin. U.S. Pat. No. 3,948,263 and U.S. Pat. No. 4,326,524 also refer to ballistic devices in which the drug is shot by 0.25-caliber rifles. In particular, U.S. Pat. No. 4,326,524 mentions drug formulations in the form of solid particles and cohesive agents that provide the projectile with enough strength to withstand firing and subsequent impact. The projectiles described have a diameter of between 4.5 and 7.6 mm and a geometry that facilitates flight. U.S. Pat. No. 3,901,158 and CA1019638 also incorporate glass or plastic ballistic devices that break on impact releasing the encapsulated active drug and its application is mainly for veterinary use.
Different to the concept of “projectiles” is the concept of “injectable needles” with dimensions and hardness that permit administration by simple pusher or injector devices in direct contact with the skin. By definition these needles must be small, have the strength and rigidity necessary for injection, and allow for the incorporation of drugs and vaccines. As an example, patent EP0139286 describes needles or bars administrated by injection and made from biocompatible organic polymers such as collagen, gelatin, albumin or chitin. The patent describes administration of these needles through hollow needles, presumably due to a lack of stiffness or hardness. The document emphasizes avoiding the immune response caused by the needle and does not suggest their potential application in the field of vaccines.
One obvious problem in the manufacture of injectable needles from aqueous or organic polymers in solution is the reduction in volume that results from the evaporation of water or solvent in the drying process. This represents a real problem in the production of needles with the desired size. Patent WO94/22423 identifies this problem and the need for needle with appropriate strength for injection, and proposes as alternative production method the extrusion from the mixture of the active ingredient with an excipients and polymers. Preferred excipients and polymers described are those soluble in aqueous media such as gelatine, collagen, cellulose, agarose or albumin. The patent does not develop in particular the applicability of needle injections into the field of vaccines. Furthermore, U.S. Pat. No. 5,081,156 and U.S. Pat. No. 4,855,134 describe interferon or indomethacin formulations incorporating collagen, gelatine or albumin as excipients and propose formulations in the form of needles or bars from the drying of a mixture or powder compression. The resulting needles seem to lack the rigidity necessary for direct injection and surgical insertion and use of catheters are described as a means for insertion. U.S. Pat. No. 5,542,920 describes simple devices for incorporation of injection needles with a pointed end and rigid enough to penetrate the skin. The needles have a preferred diameter between 0.2 and 0.8 mm and about 10 to 30 mm long. The excipients mentioned in the manufacture of the needles are preformed polymers like jelly polyvinylpyrrolidone or poly (lactic-co-glycolic acid). Neither in these documents there is a special mention of its application in the field of vaccines, nor methods for these needles to be effective in vaccination, nor the incorporation of modifying agents to increase hardness. Also, the U.S. Pat. No. 6,102,896 is also focused on the design of an injector for administering injectable soluble needles containing drugs and once again recognizes the difficulty in formulating these needles with the necessary rigidity without compromising the activity of the incorporated drug. As an example, the document recognizes the inconveniences of using phosphate or metal carboxylate glasses because of the high temperatures required for their fusion, and propose the use of sugar based powders that can be suspended in a solvent for their incorporation into narrow tubes for the manufacture of the needles.
Heterogeneous needles containing a drug either in solution or homogeneously dispersed have also been proposed as an alternative for making injectable needles with the strength required to penetrate the skin. A realization of these heterogeneous injectable needles is described in the patent WO/03023773 in which needles are composed of a soluble solid tip, followed by the drug in the form of a liquid, solid or paste. The proposed materials for the manufacture of the soluble tip include glass of sugars. The document does not provide technical solutions for the manufacture of these heterogeneous needles, but acknowledges that formulations containing residual water result in degradation of the contained actives. The devices described for administration of the proposed formulations incorporate an added complexity that can be expected to result in high-cost devices. Another realization of heterogeneous miniprojectiles is described in patent WO96/09070 and Van de Wijdeven 2002 “Development and assessment of mini projectiles as drug carriers” in the J. of Controlled Release 85:145-162 where extruded starch hollow fibres with a sharp end are filled with different drugs and vaccines and used as mini projectiles. These heterogeneous needles are large, typically 16 mm in length and 3 mm in diameter, and usually require compressed air nozzles or minor surgery for their delivery or implantation.
Injectable needles described so far have serious drawbacks. Mainly, the difficulty in manufacturing uniform needles that preserve the integrity of drug, and the difficulty in producing needles with the size shape and hardness required to pass through skin. It is therefore desirable to find a biocompatible formulation and method of manufacture that permits the efficient incorporation of drugs and vaccines in injection needles without compromising biological activity and that result in injectable needles which are sufficiently robust to be injected subcutaneously by simple pusher devices or nozzles in direct contact with skin.
The present invention relates to solid monolithic injectable needles for percutaneous, administration, including intradermal, subcutaneous or intramuscular locations, of drugs and vaccines which are partially or wholly formed by a polymer matrix resulting from a polymerization process in which drugs are incorporated. The manufacture of injectable needles by polymerization reactions described in the present invention enables fast and effective incorporation of the drugs, vaccines and other biological actives to the polymer and result in injectable needles with the optimum size, hardness and rigidity necessary to penetrate the skin. The procedures described in the present invention allow the manufacture of injectable needles that contain drugs and vaccines and may also contain modifying agents able to provide the necessary hardness to the resulting material to pass through the skin tissue under the action of a manual effort, modulate the profile of degradation of the matrix, the release profile, and/or enhance the immune response or stability of the contained drug or vaccine.